PROJECT SUMMARY/ABSTRACT Cardiovascular disease (CVD) is the leading cause of death in both men and women. The increasing rates of CVD have increased the importance of elucidating potential therapeutic treatments for this disease. Brown adipose tissue (BAT) is a thermogenic tissue that contains large amounts of mitochondria to dissipate chemical energy as heat. BAT has a high capacity for both glucose and lipid oxidation, making BAT a potential target to decrease plasma glucose and lipids and to protect against obesity and it's co-morbidities, including CVD. Increasing the amount of BAT by transplantation improves metabolic health, reduces adiposity, and improves heart function by increasing glucose uptake into the heart and providing a protective effect against experimentally-induced myocardial infarction. Exercise is a well-established therapeutic tool to improve overall heart health, and can also influence BAT activity. Our preliminary data demonstrate that exercise affects BAT activity by altering the BAT lipidome, specifically by increasing the signaling lipid 12,13-diHOME. Injection of this lipid into mice has a direct effect on the heart, increasing heart rate and left ventricular pressure. Taken together, our exciting preliminary data show that 1) transplantation of BAT increases glucose uptake into the heart; 2) exercise-training alters the lipid profile of BAT and increases the signaling lipid 12,13-diHOME; 3) injection of 12,13-diHOME in mice directly affects heart function; and 4) 12,13-diHOME is significantly increased after acute exercise in humans. These intriguing findings raise the possibility that BAT is involved in tissue-tissue communication affecting the heart. Here, we will test the novel paradigm that BAT exerts endocrine effects on the heart with three specific aims: 1) Determine if BAT exerts endocrine effects on the heart; 2) Determine if 12,13-diHOME is responsible for BAT-induced endocrine effect on the heart; and 3) Determine the mechanism through which 12,13-diHOME increases ventricular cardiomyocyte function and metabolism. This project will establish if BAT enhances heart function and metabolism, and specifically the role of the lipid 12,13-diHOME, which is released from BAT in response to exercise in both humans and rodents. The proposed studies have the potential to elucidate novel BAT-induced signaling lipids that affect the heart, which could be a new therapeutic approach to combat CVD. .